Her debut album, Home to Myself, was released in 1973; Manchester co-wrote many of its songs with Carole Bayer Sager. Two years later, Manchester's album Melissa produced her first top ten hit, "Midnight Blue", which peaked at #6 on the Billboard charts. She also performed this song on Burt Sugarman's television series Midnight Special in 1974 live. Manchester collaborated with Kenny Loggins to co-write Loggins' 1978 hit duet with Stevie Nicks, "Whenever I Call You Friend".[1] She would later record this herself for her 1979 Melissa Manchester album. At this time, she guest-starred on the CBS-TV daytime soap opera Search for Tomorrow to teach a main character, who was a singer-songwriter, the essentials of the craft. In 1979, Manchester made #10 with her version of Peter Allen's "Don't Cry Out Loud", for which she received a Grammy nomination for Best Pop Female Vocal Performance.

In 2004, Manchester returned with her first album in 10 years: When I Look Down That Road. While touring to support the album, she was praised for her still "powerful voice" and for "reinventing [herself] while staying true to what made [her] popular."[4] She appeared as herself on a two-day guest appearance on the ABC-TV daytime soap General Hospital to sing the song for Robin Scorpio and her AIDS-afflicted boyfriend Stone Cates.

Through the 1980s and 1990s Manchester alternated recording with acting, appearing with Bette Midler in the film For the Boys, on the television series Blossom,[1] and co-writing (with bookwriter-lyricist Jeffrey Sweet) and starring in the musical I Sent a Letter to My Love based on the Bernice Rubens novel of the same name. In 1990, Manchester could be heard performing "I Wish I Knew", played over the opening credits of the CBS television drama The Trials of Rosie O'Neill. In addition, she opened Game 6 of the 1991 World Series singing the U.S. National Anthem.

April 2007, she returned to the theater, starring in the Chicago production of HATS! The Musical, a show to which she had, with Sharon Vaughn, contributed two songs. Also in 2007, she recorded a duet with Barry Manilow on a cover of the Carole King classic "You've Got a Friend" on Manilow's The Greatest Songs of the Seventies.

In 2008, Manchester released a new single, "The Power of Ribbons", to digital retailers. Proceeds of the single benefit breast cancer research.

In 2011 an independent film named Dirty Girl was released with many of Manchester's songs used throughout the film, five making it on to soundtrack. Manchester made a non-speaking cameo playing the piano as the lead character Danielle sings "Don't Cry Out Loud".

In 2013, Manchester announced that she was recording her 20th studio album, her first since "When I Look Down That Road" tentatively titled You Gotta Love the Life. She subsequently launched an Indiegogo campaign to raise funds to independently release the album.[6] The new album will feature performances by Keb' Mo', Joe Sample and Dave Koz[7] in addition to a duet with Dionne Warwick and a duet called Big Light Melissa co-written with John Proulx and that she will sing with Al Jarreau.[8] In an interview with NPR, Manchester talks about the crowd-funding experience and she also relays the back-story behind the single, "Feelin' for You". A drunk in a juke joint approached Manchester and asked if she was married, in response to Manchester's, "Yes, very happily.", he replied, "Too bad, cause I got a feelin' for you."[9] "Feelin' for You", written by Manchester and Sara Niemietz, includes a solo by Keb' Mo'. The single was released on January 9, 2015 and premiered at #2 on the Smooth jazz charts.[10]You Gotta Love the Life was released on February 10, 2015,[11] and hit #17 on the Billboard Magazine Jazz Albums chart for the week of February 28, 2015.[12]

In 1980, "Through The Eyes Of Love" (from Ice Castles) and "I'll Never Say Goodbye" (from The Promise) were nominated for Academy Awards, Manchester holds the distinction of the first artist with two movie themes nominated in the same year.[1][13]

Dirty Girl (Film) (2011) - independent film that used many songs from her and she had a small non-speaking part as the piano player at the end of the film where the lead character performs "Don't Cry Outloud" in the school variety show.